DESCRIPTION (Investigators Abstract) Our brain is made of billions of neurons interconnecting through precisely aligned pre- and postsynaptic specialization. These neurons communicate with one another via regulated release of neurotransmitters. A mechanistic understanding of this neuronal communication is fundamental to our understanding of the behaviors and functions of neural networks in both normal and pathological states. Characterization of protein- protein interaction at nerve terminals has significantly advanced our knowledge of neurotransmitter release as well as vesicular transport in general. The formation of a core complex between the synaptic vesicle protein synaptobrevin and the plasma membrane proteins syntaxin and SNAP-25 has been shown to be a critical step in neurosecretion. A major challenge now is to understand how the formation of this complex is regulated to achieve the temporal and spatial specificity of synaptic vesicle docking and fusion, including synaptic plasticity. Dysregulation of this complex formation could be one of the molecular mechanisms underlying various neurological diseases and mental illness. Consistent with this view, alteration in SNAP-25 expression has been found to be associated with schizophrenia and Alzheimer's disease. As a first step towards understanding of regulation of neurotransmitter release, the applicants have identified and cloned Snapin 1 and Snapin 2, two novel proteins that interact with SNAP-25, an essential component of the neurosecretion machinery. The studies proposed herein will characterize the expression pattern and subcellular localization of Snapin 1 and Snapin 2, study their interactions with SNAP-25 and other components of the core complex, and determine the importance of these interactions in mediating synaptic vesicle trafficking and neurotransmitter release. The results from these studies will generate novel insights into the mechanism of action of SNAP-25, and make a linkage between the core complex and other regulatory components that control the temporal and spatial specificity of neurotransmitter release. Through the research proposed in this application, the applicants will define new molecular targets for understanding neurological diseases and psychiatric disorders, and provide a basis for the development of therapeutic strategies for treating malfunctions of the nervous system.